Apolipoprotein D in Oxidative Stress and Inflammation.

Apolipoprotein D (ApoD) is lipocalin able to bind hydrophobic ligands. The APOD gene is upregulated in a number of pathologies, including Alzheimer's disease, Parkinson's disease, cancer, and hypothyroidism. Upregulation of ApoD is linked to decreased oxidative stress and inflammation in several models, including humans, mice, Drosophila melanogaster and plants. Studies suggest that the mechanism through which ApoD modulates oxidative stress and regulate inflammation is via its capacity to bind arachidonic acid (ARA). This polyunsaturated omega-6 fatty acid can be metabolised to generate large variety of pro-inflammatory mediators. ApoD serves as a sequester, blocking and/or altering arachidonic metabolism. In recent studies of diet-induced obesity, ApoD has been shown to modulate lipid mediators derived from ARA, but also from eicosapentaenoic acid and docosahexaenoic acid in an anti-inflammatory way. High levels of ApoD have also been linked to better metabolic health and inflammatory state in the round ligament of morbidly obese women. Since ApoD expression is upregulated in numerous diseases, it might serve as a therapeutic agent against pathologies aggravated by OS and inflammation such as many obesity comorbidities. This review will present the most recent findings underlying the central role of ApoD in the modulation of both OS and inflammation.

Cerebral Apolipoprotein D Exits the Brain and Accumulates in Peripheral Tissues.

Apolipoprotein D (ApoD) is a secreted lipocalin associated with neuroprotection and lipid metabolism. In rodent, the bulk of its expression occurs in the central nervous system. Despite this, ApoD has profound effects in peripheral tissues, indicating that neural ApoD may reach peripheral organs. We endeavor to determine if cerebral ApoD can reach the circulation and accumulate in peripheral tissues. Three hours was necessary for over 40% of all the radiolabeled human ApoD (hApoD), injected bilaterally, to exit the central nervous system (CNS). Once in circulation, hApoD accumulates mostly in the kidneys/urine, liver, and muscles. Accumulation specificity of hApoD in these tissues was strongly correlated with the expression of lowly glycosylated basigin (BSG, CD147). hApoD was observed to pass through bEnd.3 blood brain barrier endothelial cells monolayers. However, cyclophilin A did not impact hApoD internalization rates in bEnd.3, indicating that ApoD exit from the brain is either independent of BSG or relies on additional cell types. Overall, our data showed that ApoD can quickly and efficiently exit the CNS and reach the liver and kidneys/urine, organs linked to the recycling and excretion of lipids and toxins. This indicated that cerebral overexpression during neurodegenerative episodes may serve to evacuate neurotoxic ApoD ligands from the CNS.

Infiltration of F98 glioma cells in Fischer rat brain is temporary stimulated by radiation.

PURPOSE: Irradiation of brain stimulates the expression of inflammatory mediators, some of which can modify the ability of cancer cells to infiltrate the brain. In the present study, the time window during which this stimulation occurs was determined. MATERIALS AND METHODS: Brain of Fischer rat was irradiated (15 Gy) and expression of pro-inflammatory mediators IL-1ß, IL-6 and TNF-α was measured from 4 h to 20 days post-irradiation. Level of the matrix metalloproteinase 2 (MMP-2) and prostaglandin E2 (PGE2) which can favor cancer cell infiltration were also measured. The F98 glioma cells were implanted either during (4 h post-irradiation) or after (10 days post-irradiation) the pro-inflammatory phase. Infiltration distance of F98 cells in brain parenchyma and the median survival time of the animals were determined. RESULTS: Expression of IL-1ß, IL-6 and TNF-α was significantly increased in the irradiated brains with a peak at 4 h post-irradiation. Implantation of F98 glioma cells 4 h post-irradiation reduced the median survival time of Fischer rats to 18 days, compared to 25 days when the F98 were implanted in non-irradiated brain. Irradiation of the brain increased the distance of infiltration of F98 cells and was associated with increased levels of MMP-2 and PGE2. Conversely, F98 cells implanted 10 days post-irradiation have infiltrated the brain over a shorter distance and the median survival time of rats was increased to 35 days. CONCLUSIONS: Cancer recurrence is frequently observed in GBM patients. A better understanding of the inflammatory response observed in irradiated brain could contribute to develop new therapeutic modalities to further increase the efficiency of radiotherapy.

Cyclooxygenase-2 inhibitor prevents radiation-enhanced infiltration of F98 glioma cells in brain of Fischer rat.

PURPOSE: Radiation induces a neuro-inflammation that is characterized by the expression of genes known to increase the invasion of cancer cells. In Fischer rats, brain irradiation increases the infiltration of cancer cells and reduced the median survival of the animals. In this study, we have determined whether these adverse effects of radiation can be prevented with the cyclooxygenase-2 (COX-2) inhibitor meloxicam. MATERIALS AND METHODS: Brain of Fischer rats treated or not with meloxicam were irradiated (15 Gy) and then implanted with the F98 glioma cells. The median survival of the animals, the infiltration of F98 cells, and the expression of inflammatory cytokines and pro-migration molecules were measured. RESULTS: Meloxicam reduced by 75% the production of prostaglandin E2 (bioproduct of COX-2) in irradiated brains validating its anti-inflammatory effect. Median survival was increased to control levels by the treatment of meloxicam following brain irradiation. This protective effect was associated with a reduction of the infiltration of F98 cells in the brain, a complete inhibition of radiation-enhancement of matrix metalloproteinase-2, and a significant reduction of tumor necrosis factor α (TNF-α) and tumor growth factor ß1 (TGF-ß1) expression. Using invasion chambers, interleukin-1ß (IL-1ß) stimulated by 5-fold the invasiveness of F98 cells, but this stimulation was completely inhibited by meloxicam. This suggests that a cooperation between IL-1ß and COX-2 are involved in radiation-enhancement of F98 cell invasion. CONCLUSIONS: Our results indicate the importance of reducing the inflammatory response of normal brain tissue following irradiation in an effort to extend median survival in F98 tumor-bearing rats.

Infiltration of glioma cells in brain parenchyma stimulated by radiation in the F98/Fischer rat model.

PURPOSE: In the months following radiotherapy, a rapid recurrence of glioblastoma multiforme occurs in the periphery of the resection cavity. The aim of this study was to assess the contribution of irradiation of the brain in the infiltration profile of glioma cells. MATERIAL AND METHODS: Using the F98/Fischer rat glioma model, we either irradiated the brain, the F98 cancer cells, or both to separately investigate the effects of radiation. Inflammatory cytokines and pro-infiltration molecules were measured in irradiated brain. RESULTS: A stimulation of interleukin-1ß and transforming growth factor ß1 expression 4 h after brain irradiation supported induction of inflammation. Early elevated expression of phospholipase A(2) was also measured and was followed by a stimulation of cyclooxygenase-2 from day 5 to 20 after irradiation. This resulted in a biphasic increase of prostaglandins E(2) and D(2) biosynthesis with maximum at 4 h and 15 days post-irradiation. An important enhancement of F98 cells infiltration was observed when brain was irradiated, which took place at the expense of the growth of the primary tumour and resulted in a decreased median survival of the Fischer rats. This stimulation of F98 cells infiltration was associated with the pro-infiltration molecule, matrix metalloproteinase-2. CONCLUSION: In the animal model proposed, we demonstrated that irradiation of brain increased the infiltration capacity of F98 cells to the brain, resulting in a reduction of media survival of rats bearing this tumour. This animal model has also allowed identifying inflammatory cytokines and pro-infiltration molecules induced by radiation that can be targeted to prevent this adverse effect of radiation.

Reference ranges for total and calculated free and bioavailable testosterone in a young healthy women population with normal menstrual cycles or using oral contraception.

OBJECTIVE: Determine reference values for testosterone in women. DESIGN AND METHODS: 18-40 Year-old women with regular menses or using oral contraception were assessed by questionnaire and blood sample. RESULTS: In 155 women, reference values were different between women with and without hyperandrogenism for total testosterone (0.48-3.42 vs. 0.54-2.72 nmol/L) and calculated free (3-65 vs. 3-39 pmol/L) and bioavailable (0.06-1.35 vs. 0.06-0.81 nmol/L) testosterone. CONCLUSION: Upper reference values for testosterone in women must be established from a well-characterized population.

Prevalence and predictors of vitamin D insufficiency in women of reproductive age living in northern latitude.

OBJECTIVE: This study assessed the prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD) ≤ 50 nmol/l) and insufficiency (serum 25OHD 51-74 nmol/l) during summer and the predictors of serum 25OHD in young women of reproductive age. DESIGN: Cross-sectional study. METHODS: Between May and September 2006, 153 healthy, ambulatory and essentially Caucasian women, aged 18-41 years, were recruited. Serum 25OHD and parathyroid hormone (PTH) levels were measured, and questionnaires were evaluated. RESULTS: About 3.9% of women had serum 25OHD ≤ 50 nmol/l with an additional 26.8% in the insufficient range. Most women (56.9%) had their blood sampled in September. Month of blood collection significantly influenced serum 25OHD. Body mass index (BMI) was inversely associated with serum 25OHD, while traveling to a warmer climate during winter/spring and using oral contraceptive pills (OCP) were associated with higher serum 25OHD. Sunscreen was used by 77.8% of women, but only 3.3% reported consuming vitamin D supplements. BMI, serum PTH, travel to a warmer climate, and OCP use were independently and significantly associated with serum 25OHD, after adjustment for the month of sampling, and explained 40% of the variance in serum 25OHD. CONCLUSIONS: In Canada, the prevalence of vitamin D insufficiency is relatively high (30%) during summer in healthy women of reproductive age. Given the expected decrease in serum 25OHD during winter and the low consumption of vitamin D supplements, a high prevalence of vitamin D deficiency and insufficiency is to be anticipated during winter, except maybe for those traveling to a warmer climate.